In 1992, the investigators began a population-based case-control study of ovarian cancer in eastern Massachusetts and New Hampshire to identify factors affecting risk through a pathway of oocyte-depletion and gonadotropin stimulation. Consumption and metabolism of milk sugar (galactose) was of interest based on evidence that this sugar is toxic to oocytes. Homozygosity for a mutation known as N314D of galactose transferase (GALT) or heterozygosity for mutations that more severely affect activity such as Q188R are found to increase risk for ovarian cancer, especially for endometrioid and clear cell (E/CC) types. Risk factors for these cancers also included earlier onset of, more regular, and shorter cycles--a pattern indicative of greater opportunity for retrograde menstruation and endometriosis, a possible precursor of E/CC cancers. Their search for other genetic factors revealed that 20% of ovarian cancers occurring in Jewish women at any age and 37.5% in Jewish women diagnosed <age 51 have a 185delAG mutation of BRCA1. Long term or recent oral contraceptive use was protective for ovarian cancer other than mucinous types and use of combined, but not unopposed, menopausal hormones was also protective--findings compatible with gonadotropin suppression. Talc in genital hygiene increased risk predominantly for serous and undifferentiated ovarian cancers and among those who had not had tubal ligation or hysterectomy. From their preliminary analysis, they conclude there are a variety of genetic, reproductive, and environmental risk factors for ovarian cancer which are mediated either through the ovarian-pituitary axis or through pelvic contamination with talc or menses and these risk factors vary by histologic type of ovarian cancer. They now propose continuation of this study to eventually include more than 1200 ovarian cancer cases and 1200 controls. Cases will be uniformly classified by histologic type and both germline and somatic DNA will be collected. Besides studying the above topics, several new areas will be considered. All cases and controls will be anonymously screened for BRCA1 mutations. Because cases had lower activity of another enzyme known as galactose epimerase (GALE), they will screen for newly identified mutations of this recently cloned gene. A more detailed history of analgesic use will be obtained to pursue a preliminary finding that acetaminophen use is protective for ovarian cancer. This association may be mediated through the reduction of hepatic stores of glutathione--a substance both necessary for metabolism of acetaminophen and release of FSH. Ovarian cancer pathogenesis likely involves a complex interplay among germline and somatic mutations and environmental factors. The investigators point out that only large, comprehensive epidemiologic studies capable of examining these factors within histologic subtypes are likely to succeed in identifying preventive mechanisms.